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Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer

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Melinda L. Telli, Sara M. Tolaney, Geoffrey I. Shapiro, Mark Middleton, Simon R. Lord, Hendrik Tobias Arkenau, Andrew Tutt, Vandana Abramson, Emma Dean, Tufia C. Haddad, Robert Wesolowski, Jordi Ferrer-Playan, Thomas Goddemeier, Thomas Grombacher, Jennifer Dong, Patricia Fleuranceau-Morel, Ivan Diaz-Padilla, Ruth Plummer

Original languageEnglish
Article number45
Journalnpj Breast Cancer
Volume8
Issue number1
DOIs
PublishedDec 2022

Bibliographical note

Funding Information: The authors would like to thank patients, investigators, co-investigators, and the study teams at each of the participating centers and at the healthcare business of Merck KGaA, Darmstadt, Germany. The authors thank Vertex Pharmaceuticals for their involvement in the development of berzosertib (formerly M6620, VX-970). Giuseppe Locatelli, PhD, an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, contributed to the analysis and interpretation of the biomarker results. Bart Hendriks, PhD, a former employee of the healthcare business of Merck KGaA, Darmstadt, Germany, contributed to the analysis and interpretation of PK data. Annick Seithel-Keuth, PhD, an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, contributed to the analysis and interpretation of PK data. Danyi Wang, MD, PhD, an employee of EMD Serono, Billerica, MA, USA, provided technical and operational support of biomarker sample analysis. Medical writing assistance was provided by Alexander T. Hardy of Bioscript Stirling Ltd, Macclesfield, UK and funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945 ). The trial (including acquisition of data; analysis and interpretation of data; study supervision, conception, and design; development of methodology; administrative, technical or material support; and writing, review, and/or revision of the manuscript) was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany and Vertex Pharmaceuticals Incorporated., Boston, MA, USA. Funding Information: The authors would like to thank patients, investigators, co-investigators, and the study teams at each of the participating centers and at the healthcare business of Merck KGaA, Darmstadt, Germany. The authors thank Vertex Pharmaceuticals for their involvement in the development of berzosertib (formerly M6620, VX-970). Giuseppe Locatelli, PhD, an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, contributed to the analysis and interpretation of the biomarker results. Bart Hendriks, PhD, a former employee of the healthcare business of Merck KGaA, Darmstadt, Germany, contributed to the analysis and interpretation of PK data. Annick Seithel-Keuth, PhD, an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, contributed to the analysis and interpretation of PK data. Danyi Wang, MD, PhD, an employee of EMD Serono, Billerica, MA, USA, provided technical and operational support of biomarker sample analysis. Medical writing assistance was provided by Alexander T. Hardy of Bioscript Stirling Ltd, Macclesfield, UK and funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945). The trial (including acquisition of data; analysis and interpretation of data; study supervision, conception, and design; development of methodology; administrative, technical or material support; and writing, review, and/or revision of the manuscript) was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany and Vertex Pharmaceuticals Incorporated., Boston, MA, USA. Publisher Copyright: © 2022, The Author(s).

King's Authors

Abstract

Platinum derivatives are commonly used for the treatment of patients with metastatic triple-negative breast cancer (TNBC). However, resistance often develops, leading to treatment failure. This expansion cohort (part C2) of the previously reported phase 1b trial (NCT02157792) is based on the recommended phase 2 dose of the combination of the ataxia-telangiectasia and Rad3-related (ATR) inhibitor berzosertib and cisplatin observed in patients with advanced solid tumors, including TNBC. Forty-seven patients aged ≥18 years with advanced TNBC received cisplatin (75 mg/m2; day 1) and berzosertib (140 mg/m2; days 2 and 9), in 21-day cycles. Berzosertib was well tolerated, with a similar toxicity profile to that reported previously for this combination. The overall response rate (90% confidence interval) was 23.4% (13.7, 35.8). No relevant associations were observed between response and gene alterations. Further studies combining ATR inhibitors with platinum compounds may be warranted in highly selected patient populations.

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